Resveratrol‐enhanced SIRT1‐mediated osteogenesis in porous endplates attenuates low back pain and anxiety behaviors

Abstract

Low back pain (LBP) is a major clinical problem that lacks effective treatments. The sensory innervation in porous vertebral endplates and anxiety contributes to spinal hyperalgesia. We hypothesized that SIRT1 activator resveratrol alleviates LBP and anxiety via promotion of osteogenesis in the porous endplates. The hyperalgesia and anxiety‐related behaviors; sensory innervation, inflammation and porosity of endplates; and osteogenic/osteoclastic factors expression were measured following resveratrol treatment after lumbar spine instability (LSI) surgery. To explore whether resveratrol promotes endplates osteogenesis and thus alleviates LBP through activation of SIRT1 in the osteoprogenitor cells of endplates, SIRT1OSX−/− mice were employed. Additionally, the levels of inflammation markers, phosphorylation of cAMP response element‐binding protein (pCREB), and brain‐derived neurotrophic factor (BDNF) in hippocampus were evaluated. After 4 or 8 weeks LSI surgery, the mice suffered from hyperalgesia and anxiety, which were efficiently attenuated by resveratrol at 8 weeks. Resveratrol treatment‐enhanced osteogenesis and decreased endplates porosities accompanied with the reduction of TNFα, IL‐1β, and COX2 levels and CGRP+ nerve fibers innervation in porous endplates. Resveratrol‐mediated endplates osteogenesis, decreased endplates porosities, and analgesic and antianxiety effects were abrogated in SIRT1OSX−/− mice. Furthermore, resveratrol relieved inflammation and increased pCREB and BDNF expression in the hippocampus after 8 weeks, which alleviate anxiety‐related behaviors. This study provides that resveratrol‐mediated porous endplates osteogenesis via the activation of SIRT1 markedly blocked sensory innervation and inflammation in endplates, therefore, alleviating LSI surgery‐induced LBP and hippocampus‐related anxiety.

Protective Effects of Resveratrol on Adolescent Social Isolation-Induced Anxiety-Like Behaviors via Modulating Nucleus Accumbens Spine Plasticity and Mitochondrial Function in Female Rats

“…Moreover, resveratrol could ameliorate anxiety-like behavior and social dysfunction induced by adolescent social isolation and increase NAc ATP levels as well as the number of mitochondria. Indeed, the anti-anxiety and antidepressant effects of resveratrol have been studied in a variety of animal models [ 28 ], and numerous studies demonstrated that resveratrol produces anxiolytic and antidepressant by regulating inflammation, oxidative stress, hypothalamic⁻pituitary⁻adrenal axis and neurogenesis [ 24 , 25 , 53 ]. For example, Sahin TD reported that resveratrol ameliorated streptozotocin-induced anxiety and depressive-like behaviors by inhibition of oxidative stress [ 24 ].…”

“…Another study reported that resveratrol could ameliorate social-defeat-stress-induced depressive-like behavior and locus coeruleus neuroinflammation [ 28 ]. A recent study also demonstrated that resveratrol alleviated anxiety-like behavior induced by lumbar spine instability surgery and relieved inflammation in the hippocampus [ 53 ]. Although a large number of studies have been carried out on the antidepressant mechanism of resveratrol [ 25 ], the therapeutic effect of resveratrol on adolescent depression and anxiety and the potential mechanism underlying resveratrol effects in the NAc remain largely unexplored.…”

Deciphering resveratrol's role in modulating pathological pain: From molecular mechanisms to clinical relevance

“…Overexpression of Sirt1 can modulate related signaling pathways, alleviating pathological pain (Jia et al, 2020;Li et al, 2019;Lv et al, 2021). Q.…”

“…By inhibiting cyclooxygenase activity, Sirt1 reduces inflammation and safeguards against neurological injury. Overexpression of Sirt1 can modulate related signaling pathways, alleviating pathological pain (Jia et al, 2020; Li et al, 2019; Lv et al, 2021). Q. Yin et al (2013) demonstrated that intrathecal resveratrol injections diminished mechanical allodynia and thermal nociceptive sensitization in chronic constriction injury (CCI) rats while increasing Sirt1 expression.…”

Targeting GDF15 as a potential therapy for low back pain originating from endplate

“…Drugs which could suppress the activities of osteoclasts such denosumab have shown analgesic effects in patients with Modic changes related LBP 14 . Therefore, the inhibition of osteoclastogenesis might prevent the local pathologic change and decrease the sensory innervation in endplates, which could be a potential strategy for LBP treatment 16 .…”